Inflammation and the Host Responses to Injury

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The Program seeks to improve our systems-level understanding of the key regulatory elements that direct the host response to serious injury. A greater understanding of the innate inflammatory response to serious injury will lead to the development of novel genomic and proteomic markers that can predict outcome, and will identify potential new avenues for further basic and clinical research, as well as targets for immunomodulatory interventions. The Program is organized to employ multiple high-throughput analytical tools including microarray and comparative, quantitative proteomics coupled with novel macroscale and microfluidics cell separation methodologies and bioinformatics aproaches (including knowledge-based pathway analysis). The specific aims in Years 6-10 are as follows. (1) Determine genome-wide expression and the cellular proteome from well-defined cellular subpopulations of circulating leukocytes from hospitalized patients following severe trauma and burn injuries. (2) In these cell populations, identify patterns of gene epxression and proteomic responses to the innate inflammatory response associated with different clinical trajectories and outcomes. (3) Using a systems biology approach, discover new biological knowledge based upon total cellular proteomics and genomics obtained from the cellular subpopulations. New knowledge will be obtained by fostering and supporting groups of investigators in vastly disparate disciplines, including clinicians, biochemists, immunologists, statisticians, and computational and systems biologists. These interactions will lead to the development of new paradigms for our biological understanding of the injury response. The project tasks and activities include the following: (1) enrollment of 580 severely traumatized or burned patients with stringent entry criteria and standardized guidelines for patient care; (2) high-throughput quantitative, comparative proteomic and functional proteomic analyses of enriched blood leukocyte populations; (3) genome-wide expression analysis of these same leukocyte populations using state-of-the-art high throughput formats; (4) implementation of a web-enabled trauma-related database containing clinical, physiologic, proteomic, and genomic expression data; (5) computational analysis of the complex data by data interpretation groups, comprised of biostatisticians, critical care physicians and basic scientists with the ultimate goal being an integrated systems view of the injury response.